tbuckley/cabot-search huggingface dataset:
Abstract 2513: MDSC-derived TNF is a novel regulator of T-cell dysfunction in pancreatic cancer
Authors: Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Samara Singh, Austin R. Dosch, Vanessa T. Garrido, Christine I. Rafie, Nagaraj Nagathihalli, Nipun Merchant, Jashodeep Datta
Journal: Cancer Research (2022)

Abstract Introduction: Abundance of myeloid-derived suppressor cells (MDSC) and a dysfunctional T-cell compartment are defining hallmarks of therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC). Using congenic in vivo murine models to phenocopy extremes of T-cell enrichment or exclusion, we sought to interrogate central MDSC-mediated mechanisms that govern immune tolerance in PDAC. Methods: Orthotopically implanted T-cell-excluded (Tcelllo) vs T-cell-enriched (T-cellhi) congenic KPC tumors, and intratumoral Ly6G+F4/80- MDSCs from both clones, were subjected to RNA sequencing. Ex vivo co-cultures evaluated the effects of intratumoral MDSC on splenic T-cells. Orthotopically injected KPC-T-celllo mice were treated with etanercept vs. vehicle, and immunophenotyping via flow cytometry was performed. Results: RNA-seq of KPC T-celllo vs. T-cellhi tumors revealed enrichment of myeloid immunoregulatory pathways, and downregulation of leukocyte activation/cytotoxicity pathways. Flow cytometry revealed a dramatic increase in MDSCs infiltrating KPC-Tcelllo tumors (P&amp;lt;0.001). To decipher MDSC-intrinsic mechanisms associated with T-cell exclusion, RNA-seq of MDSCs infiltrating T-cellhi clones revealed relative downregulation of MAPK signaling, and cytokine profiling of MDSCs conditioned with MAPK inhibitor trametinib revealed marked reduction in TNF secretion. Confocal microscopy confirmed striking decrease in TNF in MDSCs isolated from KPC- T-cellhi vs. Tcelllo tumors. Ex vivo MDSC-T-cell co-cultures significantly attenuated T-cell proliferation and activation (via IFN-γ release) while favoring T-cell apoptosis, which could be rescued by pre-conditioning MDSCs with either etanercept (TNFR2 decoy receptor) or MAPK pathway inhibitors. Orthotopically injected KPC-T-celllo tumor-bearing mice treated with etanercept demonstrated a remodeled TME vs. vehicle-treated mice, with attenuation in MDSC trafficking, enrichment in CD4+/CD8+ T-cell infiltration, and reduction in T-cell exhaustion. Conclusion: MDSC-derived TNF regulates T-cell dysfunction in PDAC via a MAPK-dependent mechanism. Compartment-specific inhibition of TNF may be a provocative strategy to overcome immune tolerance in PDAC. Citation Format: Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Samara Singh, Austin R. Dosch, Vanessa T. Garrido, Christine I. Rafie, Nagaraj Nagathihalli, Nipun Merchant, Jashodeep Datta. MDSC-derived TNF is a novel regulator of T-cell dysfunction in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2513.
Abstract 3647: Oncogenic Kras drives cancer-associated fibroblast heterogeneity and substate changes in pancreatic cancer
Authors: Jennifer S. Thalappillil, Giuseppina Caligiuri, Sandeep Nadella, Brinda Alagesan, Georgi N. Yordanov, Mojdeh Shakiba, Benjamin Kaminow, Juliene Hinds, Pedro A. Perez-Mancera, Jonathan Preall, Alexander Dobin, Youngkyu Park, David A. Tuveson
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is currently the third-leading cause of cancer-related deaths in the United States with no effective or targeted therapies to improve outcomes. Two defining features of PDAC are the dense stroma composing the bulk of the tumor mass and mutations in KRAS, the primary oncogene in most PDAC patients. Advances in knowledge on both fronts have led to promising avenues for therapeutics: recently described heterogeneity within the cancer-associated fibroblast (CAF) population residing in the stroma offers insight into the lack of success with therapies only targeting CAFs; and mutant KRAS inhibitors directed at the G12C isoform have received accelerated FDA approval for treatment of locally advanced and metastatic non-small cell lung cancer. However, the nature of this CAF heterogeneity is not yet fully understood, and any effects of KRAS blockade on the stroma have not been evaluated with consideration of this heterogeneity in mind. To assess how loss of Kras affects CAF heterogeneity and plasticity, we employed a genetically engineered mouse model (GEMM) of PDAC harboring a reversible oncogenic KrasG12V allele conditionally expressed from the endogenous Kras locus. This FPC compound mouse (KrasFrt-LSL-G12V-Frt; p53LSL-R172H; PDX-CRE; Rosa26FlpOERT2) spontaneously develops pancreatic lesions and allows for irreversible excision of the mutant Kras allele upon the application of Tamoxifen. Using single-cell RNA sequencing (scRNAseq), fluorescence in situ hybridization, and functional in vitro and in vivo approaches, we found that oncogenic Kras ablation led to tumor regression and altered cancer cell gene programs, profoundly affecting the tumor microenvironment, specifically CAF heterogeneity. Mutant Kras loss leads to decreased Tgfb1 expression in the cancer cells, but surprisingly also to increased Il1a levels, correlating with a reduction in myofibroblastic CAFs (myCAFs) and an expansion in inflammatory CAFs (iCAFs), respectively. Our results suggest that mutant Kras drives paracrine signaling that shapes CAF heterogeneity and should be considered for the development of the most effective therapeutic strategies. Citation Format: Jennifer S. Thalappillil, Giuseppina Caligiuri, Sandeep Nadella, Brinda Alagesan, Georgi N. Yordanov, Mojdeh Shakiba, Benjamin Kaminow, Juliene Hinds, Pedro A. Perez-Mancera, Jonathan Preall, Alexander Dobin, Youngkyu Park, David A. Tuveson. Oncogenic Kras drives cancer-associated fibroblast heterogeneity and substate changes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3647.
A dynamic 3‐factor survival model for acute myeloid leukemia that accounts for response to induction chemotherapy
Authors: Ayalew Tefferi, Naseema Gangat, Aref Al‐Kali, Hassan Alkhateeb, Mithun Shah, Mrinal S. Patnaik, Michelle A. Elliott, William J. Hogan, Mark R. Litzow, Christopher C. Hook, Abhishek Mangaonkar, David Viswanatha, Dong Chen, Animesh Pardanani, Rhett P. Ketterling, Courtney D. DiNardo, Tapan M. Kadia, Farhad Ravandi, Koji Sasaki, Kebede H. Begna
Journal: American Journal of Hematology (2022)

The current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre-treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively-treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy-related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow-up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1-4.8), adverse karyotype (2.2, 1.8-2.8), and age >55 years (2.1, 1.6-2.7) as main risk factors for survival. HR-weighted scoring resulted in four-tiered risk stratification: low (0 points; N = 183), intermediate-1 (1 point; N = 331), intermediate-2 (2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5-year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001). FLT3-ITD mutation was associated with inferior survival in intermediate-1 (p = .004) and TP53 in intermediate-2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3-ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate-1 (p < .001), intermediate-2 (p = .03), and high (p = .01) risk disease. The proposed 3-factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively-treated AML patients.
Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion
Authors: Dongwon Choi, Eunkyung Park, Roy P. Yu, Michael N. Cooper, Il-Taeg Cho, Joshua Choi, James Yu, Luping Zhao, Ji-Eun Irene Yum, Jin Suh Yu, Brandon Nakashima, Sunju Lee, Young Jin Seong, Wan Jiao, Chester J. Koh, Peter Baluk, Donald M. McDonald, Sindhu Saraswathy, Jong Y. Lee, Noo Li Jeon, Zhenqian Zhang, Alex S. Huang, Bin Zhou, Alex K. Wong, Young-Kwon Hong
Journal: Circulation Research (2022)

Background: Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. Methods: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. Results: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. Conclusions: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.
Abstract 483: Automated Ki67-LI assessment in prostate cancer using artificial intelligence in multiplex fluorescence immunohistochemistry
Authors: Niclas C. Blessin, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Maximilian Lennartz, Guido Sauter, Markus Graefen, Stefan Steurer
Journal: Cancer Research (2022)

Abstract The Ki67 labeling index (Ki67-LI) is a strong prognostic marker in prostate cancer. Its analysis requires cumbersome manual quantification of Ki67 immunostaining in at least 200 tumor cells. To enable automated Ki67-LI assessment in routine clinical practice, we have developed and validated a framework for automated Ki67-LI quantification, which comprises three different artificial intelligence analysis steps and an algorithm for cell-distance analysis of multiplex fluorescence immunohistochemistry staining. The prognostic impact of the Ki67-LI was tested on a tissue microarray (TMA) containing one sample each of 12475 prostate cancers. A “heterogeneity TMA” containing 3 to 6 samples from different tumor areas was used to model Ki67 analysis of multiple different biopsies. The Ki67-LI provided strong and independent prognostic information in 11845 successfully analyzed prostate cancers (p&amp;lt;0.001 each). The analysis of the heterogeneity TMA revealed that the Ki67-LI of the sample with the highest Gleason score (AUC:0.68) was similarly prognostic as the mean Ki67-LI of all six foci (AUC:0.71 [p=0.24]). The combined analysis of the Ki67-LI and Gleason grades obtained on identical tissue spots showed that the Ki67-LI added significant additional prognostic information in case of classical ISUP grades (AUC:0.82 [p=0.002]) and quantitative Gleason grades (AUC:0.83 [p=0.018]). The Ki67-LI is a powerful prognostic parameter in prostate cancer, which can be efficiently analyzed in multiplex fluorescence IHC. In case of multiple cancer positive biopsies, the sole analysis of the worst biopsy can be sufficient. Citation Format: Niclas C. Blessin, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Maximilian Lennartz, Guido Sauter, Markus Graefen, Stefan Steurer. Automated Ki67-LI assessment in prostate cancer using artificial intelligence in multiplex fluorescence immunohistochemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 483.
Abstract 5149: Autoantibodies to PAX5, PTCH1 and GNA11 as serological biomarkers in the detection of hepatocellular carcinoma in Hispanic Americans
Authors: Cuipeng Qiu, Xiao Wang, Bofei Wang, Yangcheng Ma, Xiaojun Zhang, Jian-Ying Zhang
Journal: Cancer Research (2022)

Abstract Liver cancer, especially hepatocellular carcinoma (HCC), is the third cause of cancer death worldwide. In the United States, it remains higher incidence rates and worse survival in the Hispanic population than the other populations. Studies have demonstrated that autoantibodies to tumor-associated antigens (TAAs) could be biomarkers with low-cost, efficient, and highly sensitive characteristics. In this study, enzyme-linked immunosorbent assay (ELISA) was conducted to measure three autoantibodies to PAX5, PTCH1, and GNA11 in sera from 25 Hispanic Americans with HCC, 28 patients with liver cirrhosis (LC), and 27 patients with chronic hepatitis (CH) as well as sera from 85 healthy individuals. At the 95% specificity for healthy controls, 56%, 48%, and 44% of HCC sera (or patients) showed elevated levels of autoantibodies to PAX5, PTCH1, and GNA11 respectively. Among the patients with LC, frequencies for autoantibodies to PAX5, PTCH1, and GNA11 were 44%, 36%, and 25% respectively. In patients with CH, the frequencies of autoantibodies to PAX5, PTCH1, and GNA11 were 22%, 22%, and 15%, which were significantly lower than those in HCC (p&amp;lt;0.01). The area under the curves (AUCs) of autoantibodies to PAX5, PTCH1, and GNA11 for identifying HCC from healthy controls were 0.912, 0.915, and 0.915, respectively. The sensitivity could be improved to 68% when three of the autoantibodies were combined with the AUC of 0.932. Therefore, autoantibodies to PAX5, PTCH1, and GNA11 showed significantly higher levels in Hispanic HCC than those in the CH or healthy controls. Also, these three autoantibodies could enhance the detection of HCC if they were combined as the parallel test. In conclusion, autoantibodies to PAX5, PTCH1, and GNA11 could be potential biomarkers for the detection of HCC in Hispanic Americans. Large size of samples is needed to further determine their potential value in clinical application. Citation Format: Cuipeng Qiu, Xiao Wang, Bofei Wang, Yangcheng Ma, Xiaojun Zhang, Jian-Ying Zhang. Autoantibodies to PAX5, PTCH1 and GNA11 as serological biomarkers in the detection of hepatocellular carcinoma in Hispanic Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5149.
Abstract 6075: ROS-Nrf2-ABCB1 axis accompanied with pFyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non-small cell lung cancer
Authors: Shigeyuki Tamari, Toshi Menju, Toshiya Toyazaki, Hideaki Miyamoto, Naohisa Chiba, Misa Noguchi, Hiroshi Date
Journal: Cancer Research (2022)

Abstract Introduction: Adjuvant cisplatin-vinorelbine is standard therapy for stage II/III lung cancer. Poor survival in lung cancer can be attributed to vinorelbine resistance arising from ABC sub-family B member 1 (ABCB1) and phosphorylated Fyn (pFyn) overexpression. However, the underlying mechanism remains unclear. Nrf2 regulates the cell-protective ABC family and activates nuclear transport of Fyn. Here, we aimed to evaluate the ROS-Nrf2-ABCB1 axis in both vinorelbine-resistant (VR) cells and clinical samples. Methods: We established VR cells by exposing H1299 cells to vinorelbine, and determined intracellular reactive oxygen species (ROS) level of H1299 cells induced by vinorelbine using DCFH-DA. We evaluated the total and subcellular expression of Nrf2, ABCB1, and pFyn in VR cells and performed immunofluorescence of VR cells to confirm the precise subcellular localization of pFyn. Cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine depends on Nrf2 activity. For immunohistochemistry, we used 104 tissue samples from lung cancer patients who underwent surgery followed by cisplatin-vinorelbine treatment between December 2006 and June 2018. Results: Persistent exposure to vinorelbine induced intracellular ROS formation of H1299 cells. Both ABCB1 and Nrf2 were overexpressed in VR cells, and ABCB1 expression was dependent on Nrf2 downstream activation. Subcellular fractionation and immunofluorescence revealed nuclear accumulation of pFyn in VR cells. Decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the 104 surgical samples, Nrf2 and ABCB1 were significantly associated with disease-free survival (p = 0.029 and 0.035, respectively), and pFyn was associated with overall survival (p = 0.040). Conclusions: ROS-Nrf2 upregulates ABCB1 and accompanied by nuclear accumulation of pFyn, induces vinorelbine resistance. Our findings may facilitate drug resistance prevention strategies or new drug target development against non-small cell lung cancer. Citation Format: Shigeyuki Tamari, Toshi Menju, Toshiya Toyazaki, Hideaki Miyamoto, Naohisa Chiba, Misa Noguchi, Hiroshi Date. ROS-Nrf2-ABCB1 axis accompanied with pFyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6075.
Abstract 2716: Cancer study of germline carriers of Inborn Errors of Metabolism (IEMs) related genes
Authors: Seokhyeon Kim, Seulki Song, Youngil Koh, Sung-Soo Yoon
Journal: Cancer Research (2022)

Abstract Inborn Errors of Metabolism (IEMs) are a hereditary disorder in which a gene fails to operate correctly as a result of a mutation in a metabolic-related gene passed down from the parents. Majority of IEMs are inherited in autosomal recessive manner. Recent research has been undertaken on mutations in numerous metabolic genes, including IEMs and cancer development. This study used Next Generation Sequencing (NGS) data to confirm the link between metabolic-related genes and cancer development in heterozygous carriers. The PCAWG (Pan-Cancer Analysis of Whole Genomes) cancer patient cohort and the 1000G (1000 Genomes) healthy cohort were used in this work, with the TCGA (The Cancer Genome Atlas) cancer patient cohorts being used for validation analysis. A regression analysis was used to determine the statistical significance of the cancer patient group versus the normal cohort. We analyzed RNA-seq data by separating heterozygous carrier and non-carrier groups of IEM related genes. The proportion of IEM gene heterozygote carriers was higher in cancer patients than in the normal population. We chose genes showing similar patterns of occurrence with statistical significance across several cancer patient cohorts. Accordingly, the most important gene, phenylalanine hydroxylase (PAH), has been established, and the carrier frequency was consistently high in lung squamous cell carcinoma (LUSC). RNA analysis results revealed that the PAH heterozygous carrier group was enriched with various immune response pathways suggesting inflammation related carcinogenesis in PAH related LUSC. Our finding suggest that heterozygote carrier status of IEM genes may lead to generation of aberrant metabolites and the breakdown of metabolic networks, which eventually leads to cancer. Citation Format: Seokhyeon Kim, Seulki Song, Youngil Koh, Sung-Soo Yoon. Cancer study of germline carriers of Inborn Errors of Metabolism (IEMs) related genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2716.
3D‐Printed Centrifugal Pump Driven by Magnetic Force in Applications for Microfluidics in Biological Analysis
Authors: Byeongwook Jo, Yuya Morimoto, Shoji Takeuchi
Journal: Advanced Healthcare Materials (2022)

In recent years, microfluidic systems have been extensively utilized for biological analysis. The integration of pumps in microfluidic systems requires precise control of liquids and effort-intensive set-ups for multiplexed experiments. In this study, a 3D-printed centrifugal pump driven by magnetic force is presented for microfluidics and biological analysis. The permanent magnets implemented in the centrifugal pump synchronized the rotation of the driving and operating parts. Precise control of the flow rate and a wide range and variety of flow profiles are achieved by controlling the rotational speed of the motor in the driving part. The compact size and contactless driving part allow simple set-ups within commercially available culture dishes and tubes. It is demonstrated that the fabricated 3D-printed centrifugal pump can induce laminar flow in a microfluidic device, perfusion culture of in vitro tissues, and alignment of cells under shear stress. This device has a high potential for applications in microfluidic devices and perfusion culture of cells.